Genetic screens are an essential tool in molecular biology, leading to the discovery of new genes and molecular pathways that are essential for health and disease regulation. RNA interference (RNAi), a natural cellular process by which short double-stranded RNA sequences target expressed genes for degradation and silencing, is widely used as a genetic screening tool. For RNAi screens, shRNA/siRNA libraries are screened for a particular cellular or physiological response. The advantage of an RNAi screen, as opposed to traditional mutagenesis, is that the shRNA hits identify the affected genes, abrogating the need for positional cloning analysis. However, RNAi screening technology is currently hampered by technical challenges. For instance, the high incidence of off-target effects complicates the identification of genuine hits. Furthermore, RNAi screens identify large numbers of hit genes, which must be validated on an individual basis by time-consuming secondary screens. In addition, there are no current methods for assessing if, or how, the hit genes interact to form cellular pathways. The present invention satisfies these needs and provides related advantages as well.